Translational control in neurons

 描述（由申请人提供）：基因表达的翻译控制是神经元形式和功能的经验依赖性长期调节中的关键机制。据推测，调控RNA在实现这一机制中发挥重要作用。突触-树枝状BC RNA通过与真核起始因子（eIF）相互作用靶向翻译机制来控制神经元蛋白质合成。所得 翻译抑制是突触强度的分子管理中的重要组成部分，因为在动物模型中缺乏BC 1 RNA会导致过度的蛋白质合成、神经元过度兴奋和致癫痫反应的倾向。 BC RNA控制的分子机制的阐明将继续构成“神经元中的翻译控制”项目的主要重点。“然而，虽然分子机制是翻译控制途径的根本基础，但现在通过解决由于先前的进展而出现的重大开放问题，将调查推向下一个层次变得非常重要。此时，三个基本问题具有最高优先级：（i）BC RNA翻译控制如何被可逆地调节，（ii）神经元如何以活性依赖性方式实现这种调节，以及（iii）这种形式的分子调节如何影响神经元功能和可塑性。 为了解决这些问题，将在三个具体目标下实施一项研究计划。第一个目标将检验eIF 4 B的磷酸化状态是BC RNA结合和翻译抑制能力的决定因素的假设。进一步假设，在神经元中，BC RNA翻译控制通过eIF 4 B磷酸化变化受到活性依赖性调节。这一机制将在目标2中从功能上加以剖析。目的3将针对BC RNA-eIF 4 B翻译控制机制在神经元功能、兴奋性和可塑性中的作用。计划项目的长期目标是从分子机制上理解突触树突状BC RNA如何实现可逆的活性依赖性翻译控制，以及这种控制如何支持神经元功能的基本形式。

 DESCRIPTION (provided by applicant): Translational control of gene expression is a key mechanism in the experience-dependent long-term modulation of neuronal form and function. It is hypothesized that regulatory RNAs play essential roles in the implementation of this mechanism. Synapto-dendritic BC RNAs control neuronal protein synthesis by targeting the translation mechanism through interactions with eukaryotic initiation factors (eIFs). The resulting translational repression is an important component in the molecular management of synaptic strength as lack of BC1 RNA in animal models causes excessive protein synthesis, neuronal hyperexcitability, and a propensity for epileptogenic responses. The elucidation of molecular mechanisms of BC RNA control will continue to constitute a major emphasis of the project "Translational control in neurons." However, while molecular mechanisms are fundamental underpinnings of translational control pathways, it will now become important to move the investigation to the next level by addressing significant open issues that have come to the fore as a result of previous advances. Three fundamental questions are commanding highest priority at this time: (i) how is BC RNA translational control reversibly modulated, (ii) how do neurons implement such modulation in an activity- dependent manner, and (iii) how does this form of molecular regulation impact neuronal function and plasticity? To address these questions, a Research Plan will be implemented in three Specific Aims. The first Aim will test the hypothesis that the phosphorylation status of eIF4B is a determinant of BC RNA binding and translational repression competence. It is further hypothesized that in neurons, BC RNA translational control is subject to activity-dependent modulation via eIF4B phosphorylation changes. This mechanism will be functionally dissected in Aim 2. Aim 3 will be directed at the role of the BC RNA - eIF4B translational control mechanism in neuronal function, excitability, and plasticity. It will be the long-term goal of the planned project to arrive at a molecular-mechanistic understanding of how reversible, activity-dependent translational control is implemented by synapto-dendritic BC RNAs, and how such control supports elemental forms of neuronal functionality.